The genetic basis of major depressive disorder

Abstract

The genetic dissection of major depressive disorder (MDD) ranks as one of the success stories of psychiatric genetics, with genome-wide association studies (GWAS) identifying 178 genetic risk loci and proposing more than 200 candidate genes. However, the GWAS results derive from the analysis of cohorts in which most cases are diagnosed by minimal phenotyping, a method that has low specificity. I review data indicating that there is a large genetic component unique to MDD that remains inaccessible to minimal phenotyping strategies and that the majority of genetic risk loci identified with minimal phenotyping approaches are unlikely to be MDD risk loci. I show that inventive uses of biobank data, novel imputation methods, combined with more interviewer diagnosed cases, can identify loci that contribute to the episodic severe shifts of mood, and neurovegetative and cognitive changes that are central to MDD. Furthermore, new theories about the nature and causes of MDD, drawing upon advances in neuroscience and psychology, can provide handles on how best to interpret and exploit genetic mapping results.

Mechanistic convergence of depression and suicidality on astrocyte fatty acid metabolism

“…Furthermore, we identify PPARA as a putative anti-depressant target to modulate these mechanisms. Considering the diffuse definitions of MDD used in GWAS 51 and the limitations of TWAS 5 , we illustrate that integrating results across data modalities and using orthogonal methods is a viable strategy for the delineation of therapeutically actionable mechanisms in MDD.…”

Transcription factor activity profiling reveals the role of REST and LEF1 in the recovery from depression

“…The pathophysiology of depression remains incompletely understood, primarily due to our limited comprehension of the disease’s pathogenic heterogeneity ( 14 ). Our observations suggests that previously unrecognized targets of antidepressants may affect the clinical outcomes of those therapeutics.…”

“…These observations suggest that plastic changes in the brain are involved in both the pathogenesis of the disease and its therapeutic response. Although several genes have been suggested to play a role in the development of the disease, our complete understanding of the pathophysiology of depression is still in its infancy, due to the involvement of multiple genes and their interaction with environmental risk factors ( 2 , 10 , 14–16 ).…”

The Melanocortin System: A Promising Target for the Development of New Antidepressant Drugs

“…The heritability of depression is estimated at 31–42% [ 5 , 6 ]. Despite the identification of genetic loci thought to increase the risk of developing depression, genome-wide association studies have not led to the discovery of genes associated with the development of this mental disorder [ 7 , 8 , 9 , 10 ]. Transcriptome-wide association studies indicate changes in the expression of a large number of genes in depression [ 11 , 12 , 13 ].…”